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A simple synthetic method of SEM-CI, an important intermediate of anti-myelofibrosis ruxolitinib

A technology of myelofibrosis and synthesis method, which is applied in the field of organic synthesis, can solve the problems of severe reaction, low purity and difficult preservation, and achieves the effects of improving reaction efficiency, simple and convenient operation and stable quality.

Inactive Publication Date: 2019-04-19
南京诺希生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there will still be water production during the first step of the reaction, which will destroy the intermediate, generate impurities, and reduce the yield.
In the second step of replacement, when butyllithium is used alone, the alkalinity is too strong, and there will be a large amount of impurities replaced by chlorine, which will seriously affect the yield and purity of the product.
The reaction is violent, it is difficult to control, and the cost of lithium aluminum hydride is very high, the operation is dangerous, and the post-processing is difficult. The entire cost of this process is very high
(2) The raw material chloromethyltrimethylsilane used is expensive and the cost is higher
However, the product is unstable under acidic conditions, so that the total yield of the product prepared by this process is not high, the purity is not high, and it is not easy to store

Method used

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  • A simple synthetic method of SEM-CI, an important intermediate of anti-myelofibrosis ruxolitinib
  • A simple synthetic method of SEM-CI, an important intermediate of anti-myelofibrosis ruxolitinib
  • A simple synthetic method of SEM-CI, an important intermediate of anti-myelofibrosis ruxolitinib

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Experimental program
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Effect test

Embodiment 1

[0038] Take 500g of 2-bromoethanol, 500ml of petroleum ether, 130g of paraformaldehyde, and 80g of concentrated sulfuric acid, put them into a 2L reaction bottle, and start stirring. The system was cooled to -5-0°C, and HCL gas was introduced. Introduce slowly at the beginning, after about 10 minutes, increase the aeration rate, control the internal temperature at 5-8°C, and slow down the aeration rate again when the reaction solution becomes clear. The gas phase is monitored until the raw material is less than 5%, and the aeration is stopped (about 240 g of shared hydrogen chloride). Add 1 g of dimethylethylamine to the reaction liquid, and stir for 5 min. The layers were separated, and the lower layer was extracted once with 500ml petroleum ether, and the organic phases were combined. Concentrate under reduced pressure at 50°C (recovery of petroleum ether) until there is no bubble and no reflux to obtain the crude product. 60-90 ° C, water pump rectification, to obtain th...

Embodiment 2

[0040] Take 5000g of 2-bromoethanol, 5000ml of petroleum ether, 1300g of paraformaldehyde, and 800g of concentrated sulfuric acid, put them into a 20L reaction bottle, and start stirring. The system was cooled to -5-0°C, and HCL gas was introduced. Introduce slowly at the beginning, after about 10 minutes, increase the aeration rate, control the internal temperature at 5-8°C, and slow down the aeration rate again when the reaction solution becomes clear. The gas phase is monitored until the raw material is less than 5%, and the aeration is stopped (about 2500 g of shared hydrogen chloride). Add 10 g of triethylamine to the reaction liquid, and stir for 5 min. The layers were separated, and the lower layer was extracted once with 500ml petroleum ether, and the organic phases were combined. Concentrate under reduced pressure at 50°C (recovery of petroleum ether) until there is no bubble and no reflux to obtain the crude product. 60-90°C, water pump rectification, 4.96kg of th...

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Abstract

The invention discloses a simple synthetic method of SEM-CI, an important intermediate of anti-myelofibrosis ruxolitinib. A chloromethylation intermediate is synthesized by taking 2-bromoethanol as amain raw material, petroleum ether as a solvent, polyformaldehyde and hydrogen chloride as chloromethylation reagents and concentrated sulfuric acid as a water absorbing agent; A complex of Grignard reagent and butyllithium is used as base extraction bromide and reacts with trimethylchlorosilane to synthesize the target product in two steps. The simple synthetic method of the invention has the advantages of easily available raw materials, low cost, simple and convenient operation, high yield, less ''three wastes '', reasonable process and stable quality.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a simple and convenient synthesis method of an important intermediate SEM-Cl of anti-myelofibrosis ruxolitinib. Background technique [0002] Myelofibrosis is a myeloproliferative disease caused by collagen hyperplasia in bone marrow hematopoietic tissue, and its fibrous tissue seriously affects hematopoietic function. It is a kind of malignant leukemia, and there is no specific drug at present. Ruxolitinib, as a drug that has a good effect on myelofibrosis, has attracted the attention of people in the medical field since its inception, and it is very hopeful that it will become a specific drug for myelofibrosis. In the synthesis of ruxolitinib, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl), as an important intermediate, plays a major role in the final quality and price of the drug. At the same time, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl), as a...

Claims

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Application Information

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IPC IPC(8): C07F7/08
CPCC07F7/0827
Inventor 赵小林崔家乙赵兵艾杨保汪金柱廖朝庭
Owner 南京诺希生物科技有限公司
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